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EGFR Combination Therapy Should Become the New Standard First-Line Treatment in Advanced EGFR-Mutant NSCLC

*October 2021*

The discovery of the EGFR driver mutation, and the subsequent development of EGFR-targeted therapy, has drastically changed the treatment and prognosis of this subgroup of patients with metastatic NSCLC. More recently, targeted therapy is also changing the treatment paradigm and outcomes for patients with early stage disease.1 Although targeted therapy with EGFR tyrosine kinase inhibitors (TKIs) is initially highly effective, patients will inevitably develop resistance. Recent data on combination strategies reveal the ability to delay the development of resistance and improve outcomes in these patients.

Single-agent osimertinib is a typically used first-line treatment option for patients with metastatic EGFR-mutated (EGFRm) NSCLC, on the basis of the results of the FLAURA trial.2 In this phase 3 study, patients with classic EGFR mutations were randomized to osimertinib 80 mg daily (n = 279) or gefitinib/erlotinib at standard doses (n = 277). Progression-free survival (PFS) was longer with osimertinib (median = 18.9 mo versus 9.2 mo, p < 0.001), as was overall survival (OS) (median = 38.6 mo versus 31.8 mo, p = 0.046). It is important to recognize that of the patients who discontinued osimertinib, only 60% went on to receive further systemic therapy. The most common reason for not receiving subsequent therapy was death. The significant drop-off found in the proportion of patients eligible for treatment with each subsequent line of therapy highlights the need to use the most effective treatments upfront.

Despite the advent of EGFR TKIs, cytotoxic chemotherapy still plays a significant role in the management of advanced EGFRm NSCLC. EGFRm NSCLC may be more sensitive to chemotherapy compared with wild-type disease, with doubling of response rates to platinum-doublet chemotherapy found in the pivotal IPASS (First Line IRESSA™ Versus Carboplatin/Paclitaxel in Asia) study.3 Chemotherapy and EGFR TKIs may have a synergistic effect through combined reduction in vascular endothelial growth factor (VEGF)–mediated angiogenesis,4 and with EGFR TKIs counteracting chemotherapy-induced up-regulation of downstream EGFR signaling.4,5 The combination may also delay the development of clinical resistance through a greater induction of apoptosis in EGFR TKI-resistant cell populations5 and by limiting tumor heterogeneity.6 There have been two large trials evaluating the combination of gefitinib and chemotherapy versus gefitinib alone for first-line treatment of metastatic EGFRm NSCLC, both revealing a significant OS benefit with the combination. Read more.